1P42

Crystal structure of Aquifex aeolicus LpxC Deacetylase (Zinc-Inhibited Form)

Summary for 1P42

• Entry DOI: 10.2210/pdb1p42/pdb
• Descriptor: UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase, ZINC ION, MYRISTIC ACID, ... (4 entities in total)
• Functional Keywords: alpha+beta fold, hydrophobic tunnel, hydrolase
• Biological source: Aquifex aeolicus
• Total number of polymer chains: 2
• Total formula weight: 62631.23

Authors

Whittington, D.A.,Rusche, K.M.,Shin, H.,Fierke, C.A.,Christianson, D.W. (deposition date: 2003-04-21, release date: 2003-06-10, Last modification date: 2024-02-14)

Primary citation

Whittington, D.A.,Rusche, K.M.,Shin, H.,Fierke, C.A.,Christianson, D.W.
Crystal Structure of LpxC, a Zinc-Dependent Deacetylase Essential for Endotoxin Biosynthesis
Proc.Natl.Acad.Sci.USA, 100:8146-8150, 2003

PubMed Abstract: The outer leaflet of the outer membrane of the Gram-negative bacterium serves as a permeability barrier and is composed of lipopolysaccharide, also known as endotoxin. The membrane anchor of lipopolysaccharide is lipid A, the biosynthesis of which is essential for cell viability. The first committed step in lipid A biosynthesis is catalyzed by UDP-(3-O-(R-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase (LpxC), a zinc-dependent deacetylase. Here we report the crystal structure of LpxC from Aquifex aeolicus, which reveals a new alpha+beta fold reflecting primordial gene duplication and fusion, as well as a new zinc-binding motif. The catalytic zinc ion resides at the base of an active-site cleft and adjacent to a hydrophobic tunnel occupied by a fatty acid. This tunnel accounts for the specificity of LpxC toward substrates and inhibitors bearing appropriately positioned 3-O-fatty acid substituents. Notably, simple inhibitors designed to target interactions in the hydrophobic tunnel bind with micromolar affinity, thereby representing a step toward the structure-based design of a potent, broad-spectrum antibacterial drug.

PubMed: 12819349
DOI: 10.1073/pnas.1432990100

Experimental method

X-RAY DIFFRACTION (2 Å)